We have made the exciting discovery that a mutation in the first circadian clock gene to be discovered in mammals, clock, not only alters circadian and sleep phenotypes, but also leads to obesity and diabetes. The major phenotypic changes that have been observed in homozygous Clock mutant animals are: 1) an initial 4 hr lengthening of the free-running period of the circadian clock under constant lighting conditions which often is followed by the total loss of rhythmicity, 2) a 1-2 hr decrease in total sleep time under both entrained and free-running conditions, 3) age-related increased weight, and 4) age-related hyperglycemia. The development of the Clock mouse in our laboratories, and the positional cloning of the transcription factor (CLOCK) encoded by this gene, provides a new genetic model to examine the link between the circadian clock, sleep loss and age-related metabolic disease at a molecular level. In the proposed studies we will test hypotheses that will determine whether obesity and diabetes arise in Clock mutant mice due to alterations in central nervous system function or effects of the clock gene on peripheral endocrine homeostasis. One overall objective will be to investigate the effect of the clock gene mutation on feeding behavior, body adipose composition, circulating leptin and insulin levels and energy utilization (Specific Aims #1 and #2), in order to determine the cause of obesity in these animals. We will further dissect the mechanisms leading to weight gain by examining the effect of the clock mutation on orexigenic and anorexigenic hypothalamic signaling pathways in Clock mutant mice (Specific Aim #3). Finally, we will test the hypothesis that obesity and diabetes develop due to effects of the circadian clock mutation on the suprachiasmatic nucleus (SCN) by studying measures of weight, energy expenditure and glucose metabolism in Clock mutant and wild-type animals after electrolytic ablation of the SCN. These experiments will be the first to examine the combined effects of the clock gene mutation on sleep-wake homeostasis and metabolic function. The proposed studies will also provide a novel model for the identification of targeted interventions for the treatment and prevention of the adverse effects of sleep loss in the aging population.